Of the potential organisms that might be used in bioterrorism, smallpox would likely have the most horrific impact on the health of the U.S. Small pox is highly Contagious and mortality is in the range of 30%. There is no available antiviral therapy. Furthermore, the U.S. population is essentially entirely susceptible because routine immunization was terminated in the early 1960's. Even older vaccines are vulnerable as vaccine protection wanes significantly after ten years. As a result of the eradication of the disease, and with the exception of the development of fowlpox vaccine vectors, the amount of research on smallpox and related poxviruses has decreased significantly. This proposal will support the acquisition and analysis of orthopoxvirus genomic information to facilitate its application to the development of therapies and improved vaccines for smallpox and related viruses. The goals of the project are: 1) Collect and/or determine the genomic sequences of variola virus isolates and orthopoxviruses that might serve as surrogates for variola virus in animal models; 2) Design and maintain a relational database to store, display, annotate and query genome sequence, structural information, phenotypic data (e.g. drug susceptibility, virulence, host specificity) and bibliographic information; 3) Apply innovative methods for global functional analysis of the viral genomes; 4) Serve as a repository of well-documented viral strains (including clinical isolates and mutants, if relevant) and genomic clones that are used in the genomic sequence analysis; and 5) Develop and maintain a website.